Heterocyclic 5-lipoxygenase inhibitors

Abstract

The invention concerns an aryl derivative of the formula I, <IMAGE> I wherein Ar1 is optionally substituted phenyl, naphthyl or a heterocyclic moiety, and X1 is oxy, thio, sulphinyl, sulphonyl, difluoromethylene, imino, (1-4C)alkylimino or optionally substituted (1-4C)alkylene, or X1 is a group of the formula -X4-CR2- or -CR2-X4- wherein X4 is oxy, thio, sulphinyl, sulphonyl or carbonyl and each R is hydrogen, methyl or ethyl; each of Ar2 and Ar3 is optionally substituted phenylene; X2 is oxy, thio, sulphinyl or sulphonyl; R1 is (1-4C)alkyl; and R2 and R3 together form a group of the formula -A1-X3-A2- which together with the carbon atom to which A1 and A2 are attached define a ring having 5 to 7 ring atoms, wherein each of A1 and A2 is (1-3C)alkylene and X3 is oxy, thio, sulphinyl or sulphonyl; which compounds are inhibitors of 5-lipoxygenase and are useful in the treatment of inflammatory or allergic disease.

We claim: 
     
       1. An aryl derivative of the formula I wherein   Ar 1  is a 5- or 6-membered monocyclic heterocyclic moiety each containing one or two nitrogen heteroatoms, or a hydrogenated derivative thereof, which heterocyclic moiety may optionally bear one, two or three substituents selected from halogeno, hydroxy, cyano, trifluoromethyl, oxo, thioxo, (1-4C)alkyl and (1-4C)alkoxy, and X 1  is oxy, thio, sulphinyl, sulphonyl, carbonyl or (1-4C)alkylene, and wherein the (1-4C)alkylene group may optionally bear one or two substituents selected from hydroxy, (1-4C)alkyl and (1-4C)alkoxy;   Ar 2  and Ar 3 , which may be the same or different, each is phenylene which may optionally bear one or two substituents selected from halogeno, hydroxy, amino, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;   X 2  is oxy, thio, sulphinyl or sulphonyl;   R 1  is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and   R 2  and R 3  together form a group of the formula --A 1  --X 3  --A 2  -- which together with the carbon atom to which A 1  and A 2  are attached define a ring having 6 ring atoms, wherein A 1  and A 2 , which may be the same or different, each is (1-3C)alkylene and X 3  is oxy, and which ring may bear one or two substituents selected from hydroxy, (1-4C)alkyl and (1-4C)alkoxy; or a pharmaceutically-acceptable salt thereof.     
     
     
       2. An aryl derivative of the formula I as claimed in claim 1 wherein Ar 1  is a 5- or 6-membered monocyclic heterocyclic moiety each containing one or two nitrogen heteroatoms, or a hydrogenated derivative thereof, which heterocyclic moiety may optionally bear one, two or three substituents selected from halogeno, hydroxy, cyano, trifluoromethyl, oxo, thioxo, (1-4C)alkyl and (1-4C)alkoxy, and X 1  is oxy, thio, sulphinyl, sulphonyl, carbonyl or (1-4C)alkylene, and wherein the (1-4C)alkylene group may optionally bear one or two substituents selected from hydroxy, (1-4C)alkyl and (1-4C)alkoxy;   Ar 2  and Ar 3 , which may be the same or different, each is phenylene which may optionally bear one or two substitutes selected from halogeno, hydroxy, amino, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;   X 2  is oxy, thio, sulphinyl or sulphonyl;   R 1  is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and   R 2  and R 3  together form a group of the formula --A 1  --X 3  --A 2  -- which together with the carbon atom to which A 1  and A 2  are attached define a ring having 6 ring atoms, wherein A 1  and A 2 , which may be the same or different, each is (1-3C)alkylene and X 3  is oxy, and which ring may bear one or two substituents selected from hydroxy, (1-4C)alkyl and (1-4C)alkoxy; or a pharmaceutically-acceptable salt thereof.     
     
     
       3. An aryl derivative of the formula I as claimed in claim 1 wherein Ar 1  is 1-pyrrolyl, 1-pyrazolyl, 3-pyridyl, 2-oxo-1,2-dihydropyrid-1-yl or 4-oxo-1,4-dihydropyrid-1-yl;   X 1  is carbonyl or methylene;   Ar 2  is 1,4-phenylene which may optionally bear one substituent selected from fluoro, chloro, methyl and methoxy;   X 2  is thio;   Ar 3  is 1,3-phenylene which may optionally bear one or two substituents selected from fluoro, chloro, trifluoromethyl and methyl;   R 1  is methyl or ethyl; and   R 2  and R 3  together form a group of the formula --A 1  --X 3  --A 2  -- which together with the carbon atom to which A 1  and A 2  are attached define a ring having 6 ring atoms, wherein A 1  is ethylene, A 2  is ethylene and X 3  is oxy, and which ring may bear one or two methyl substituents; or a pharmaceutically-acceptable salt thereof.     
     
     
       4. An aryl derivative of the formula I as claimed in claim 1 wherein Ar 1  is 1-pyrrolyl or 3-pyridyl;   X 1  is carbonyl or methylene;   Ar 2  is 1,4-phenylene;   X 2  is thio;   Ar 3  is 1,3-phenylene or 5-fluoro-1,3-phenylene;   R 1  is methyl; and   R 2  and R 3  together form a group of the formula --A 1  --X 3  --A 2  -- which together with the carbon atom to which A 1  and A 2  is attached define a ring having 6 ring atoms, wherein A 1  is ethylene, A 2  is ethylene and X 3  is oxy, and which ring may bear a methyl substituent alpha to X 3  ; or a pharmaceutically-acceptable salt thereof.     
     
     
       5. An aryl derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in claim 1 being: 4-methoxy-4-[3-(4-pyrrol-1-ylmethyl)phenylthio)phenyl]tetrahydropyran.   
     
     
       6. A pharmaceutical composition suitable for use in providing inhibition of 5-lipoxygenase which comprises an effective amount of an aryl derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 5 in association with a pharmaceutically-acceptable diluent or carrier. 
     
     
       7. A method of treating an inflammatory or allergic condition in a warm-blooded animal in need of such treatment which comprises administering to said warm-blooded animal a 5-lipoxygenase inhibitory amount of an aryl derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 5.